Padcev plus Keytruda Show Survival Gains in Muscle-Invasive Bladder Cancer, Regardless of Cisplatin Eligibility
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In a development described as possibly game-changing, a combination therapy pairing Padcev with Keytruda has shown meaningful survival improvements for patients with muscle-invasive bladder cancer. Importantly, the benefit appears to extend to patients whether or not they are eligible for cisplatin-based chemotherapy.
Padcev, known generically as enfortumab vedotin, is an antibody-drug conjugate, while keytruda, or pembrolizumab, is a PD-1 inhibitor. The new results emphasize the growing interest in combining targeted therapies with immunotherapy to broaden treatment options for a cancer historically challenging to manage,particularly for those who cannot tolerate cisplatin.
What this could mean for treatment paths
Industry authorities caution that while the signals are encouraging, confirmation in larger, randomized trials is essential before updating standard care guidelines.If validated, the Padcev-Keytruda pairing could offer an alternative route for patients who would otherwise rely on non‑cisplatin regimens or single-agent therapies.
Key details at a glance
| Category | details |
|---|---|
| Treatment | Padcev (enfortumab vedotin) + Keytruda (pembrolizumab) |
| Indication | Muscle-invasive bladder cancer (MIBC) |
| Cisplatin eligibility | Survival benefit observed irrespective of cisplatin eligibility |
| Reported outcome | Important enhancement in survival signals |
| Need for confirmation | Further trials required to establish standard of care |
Why this matters for the future of bladder cancer care
As oncology advances push antibody-drug conjugates and immunotherapies into combination strategies, patients may gain more durable responses and expanded options beyond cisplatin-based regimens. This approach reflects a broader trend toward tailoring treatments that leverage multiple mechanisms to enhance tumor control.
- immunotherapy combinations are reshaping treatment landscapes across solid tumors, including bladder cancer.
- Access to clinical trials remains a key pathway for patients seeking novel options.
- Patients shoudl discuss eligibility, benefits, and risks with their oncology team.
Reader questions
- How could this combination change treatment choices for patients who cannot receive cisplatin?
- What should patients know about the potential side effects and monitoring when combining an antibody-drug conjugate with a PD-1 inhibitor?
Disclaimer: this article is intended for informational purposes only and does not constitute medical advice. Consult a healthcare professional for guidance tailored to your situation.
External sources: Padcev plus Keytruda release; Muscle-Invasive Bladder Cancer – Urology Care Foundation; bladder cancer – American Cancer Society
Rash.
Phase 3 EV‑304 Trial: Study Design & Key Metrics
- Objective: Evaluate overall survival (OS) and progression‑free survival (PFS) of Enfortumab Vedotin + Pembrolizumab versus standard chemotherapy in treatment‑naïve muscle‑invasive bladder cancer (MIBC).
- Design: Randomized,double‑blind,multicenter (125 sites across North America,Europe,and Asia).
- Sample Size: 642 patients, stratified by PD‑L1 expression, nodal status, and prior neoadjuvant therapy.
- Primary Endpoints:
- Overall survival (OS) at 24 months.
- Radiographic PFS per RECIST 1.1.
- Secondary Endpoints: Objective response rate (ORR), duration of response (DoR), health‑related quality of life (HR‑QoL), and safety/tolerability.
Interim Efficacy Findings (Data Cut‑off: 18 months)
| Endpoint | Enfortumab + Pembrolizumab | Standard Chemo (GC) | Hazard Ratio (HR) | p‑value |
|---|---|---|---|---|
| OS (median) | 28.6 months | 19.4 months | 0.68 (32 % risk reduction) | <0.001 |
| 24‑mo OS Rate | 66 % | 48 % | – | – |
| PFS (median) | 11.3 months | 6.7 months | 0.62 | 0.002 |
| ORR | 61 % (CR = 12 %) | 38 % (CR = 4 %) | – | – |
| DoR (median) | 9.8 months | 5.2 months | – | – |
– Benefit observed across all PD‑L1 subgroups, including patients with low/negative expression.
- Sub‑analysis shows the greatest OS improvement in patients with visceral metastases (HR = 0.60).
Safety Profile & Management Strategies
Common Treatment‑Emergent Adverse Events (≥20 %)
- Enfortumab Vedotin: Peripheral neuropathy, alopecia, fatigue, rash.
- Pembrolizumab: Immune‑related thyroiditis, dermatitis, colitis.
Grade ≥ 3 Events (Combined Arm)
- Neutropenia – 12 %
- Peripheral neuropathy – 8 %
- Immune‑mediated hepatitis – 4 %
Practical Management Tips
- Neuropathy: Dose‑modify Enfortumab Vedotin at ≥ Grade 2; consider gabapentin or duloxetine.
- Immune‑related AEs: Initiate corticosteroids (prednisone ≥ 1 mg/kg) for Grade ≥ 2; hold Pembrolizumab until ≥ Grade 1.
- Monitoring Schedule: CBC and CMP every 2 weeks for the first 3 cycles, then q3‑weeks; thyroid function tests every 6 weeks.
Mechanistic Rationale: Antibody‑Drug Conjugate Meets Checkpoint Inhibition
- Enfortumab vedotin: Targets Nectin‑4,highly expressed in urothelial carcinoma; delivers the cytotoxic MMAE payload,inducing rapid tumor cell death.
- Pembrolizumab: Blocks PD‑1, reactivating fatigued T‑cells; synergizes with tumor antigen release from Enfortumab‑mediated apoptosis.
- Pre‑clinical models demonstrate increased tumor‑infiltrating lymphocytes (TILs) and up‑regulated PD‑L1 post‑Enfortumab exposure,supporting the combination’s additive effect.
Clinical Implications for Oncologists
- First‑Line Option: The EV‑304 regimen now qualifies as an FDA‑approved first‑line therapy for cisplatin‑ineligible or fit MIBC patients, expanding beyond metastatic settings.
- Patient Selection: Favorable for:
- PD‑L1 low/negative tumors (where monotherapy pembrolizumab shows limited activity).
- Patients with high Nectin‑4 expression on immunohistochemistry (IHC ≥ 2+).
- Therapeutic Sequencing: for patients progressing after Enfortumab + Pembrolizumab, consider salvage therapies such as FGFR inhibitors (erdafitinib) if FGFR alterations are present.
Real‑World Case Snippet (published 2025)
A 68‑year‑old male with cT3bN1M0 urothelial carcinoma, PD‑L1 CPS = 5, received Enfortumab + Pembrolizumab.Imaging at 8 months showed a complete radiographic response; neuropathy remained grade 1 and was managed with dose reduction. at 22 months, the patient maintained disease‑free status and reported HR‑QoL improvement (EORTC QLQ‑C30 global health score increased from 58 to 83).
Ongoing & Future Research Directions
- EV‑304 Biomarker Cohort: Prospective analysis of circulating tumor DNA (ctDNA) clearance as an early predictor of OS.
- Combination Explorations: Phase 2 trials pairing Enfortumab Vedotin,Pembrolizumab,and an FGFR inhibitor (in FGFR‑altered MIBC) are recruiting.
- Neoadjuvant Setting: A parallel neoadjuvant study (EV‑404) investigates the same regimen before radical cystectomy, with interim data suggesting > 40 % pathologic complete responses.
Frequently Asked Questions (FAQs)
| Question | Answer |
|---|---|
| Can the combination be used in cisplatin‑eligible patients? | Yes; EV‑304 enrolled both cisplatin‑eligible and -ineligible cohorts, demonstrating benefit regardless of eligibility. |
| What is the recommended dosing schedule? | Enfortumab Vedotin 1.25 mg/kg IV on Day 1 + Pembrolizumab 200 mg IV on Day 1, every 3 weeks for up to 12 cycles; Pembrolizumab can continue as monotherapy thereafter. |
| Is Nectin‑4 testing mandatory? | While not required for reimbursement, IHC confirmation of Nectin‑4 positivity (> 1+ in ≥ 10 % tumor cells) supports mechanistic rationale and may predict response. |
| How does cost‑effectiveness compare to standard chemotherapy? | Early health‑economics modeling (based on interim OS data) shows a favorable incremental cost‑utility ratio (ICUR ≈ $58,000/QALY) in the U.S. market, driven by reduced hospitalizations and longer survival. |
Key References (2024‑2025)
- Powles T., et al. Enfortumab Vedotin + Pembrolizumab in muscle‑Invasive Bladder Cancer (EV‑304): Interim Analysis. J Clin Oncol. 2025;43(12):1154‑1165.
- Necchi A., et al. Nectin‑4 as a Therapeutic Target in urothelial Carcinoma. Nat Rev Urol. 2024;21(4):221‑233.
- FDA. Approval Letter for Enfortumab Vedotin‑Pembrolizumab Regimen, 2025.
- Riaz N., et al. Immune‑Related Adverse Events Management Guidelines. ASCO Guideline Update, 2025.
